Within the mammalia bats are second only to rodents in species diversity. The taxonomic order of bats is Chiroptera, further classified into the suborders Megachiroptera and Microchiroptera, usually referred to as fruit bats or megabats and insectivorous bats or microbats, respectively. The Megachiroptera contains a single family, the Pteropodidae, whereas the Microchiroptera are subdivided into seven superfamilies comprising a total of seventeen families.
Greater taxonomic complexity of microbats is mirrored in their worldwide geographic distribution that includes temperate climate zones and the Americas compared to megabats that are confined to tropical and subtropical regions of the Eastern Hemissphere.
Microbats have tails and one clawed finger on each wing, megabats generally have no tail and two clawed fingers on each wing. Megabats have simple ears with the rim of the pinnae forming a closed ring and simple snouts without the complicated nose leaves supporting production of echolocation signals. Microbats are insectivorous, hunt small animals or feed on blood. Megabats are frugivorous or nectarivorous.
Microbats but not megabats are able to perform echolocation for orientation and to avoid obstacles. Megabats rely on their acute sense of vision; indeed, only in megabats (but not in microbats) neuronal organisation connecting retina and midbrain appears just as advanced as it is in primates (Pettigrew 1986 in Science 231, 1304-1306). As the single exception within the megabats Rousettus aegyptiacus is also capable of sonar orientation. However, the echolocation system of Rousettus is not related to the sophisticated laryngeal echolocation of the microbats (Springer 2001 et al. in Proc. Natl. Acad. Sci. U.S.A. 96, 6241-6246; Holland et al. 2004 in J. Exp. Biol. 207, 4361-4369). It is the result of convergent evolution and comparatively simple where the emitted signal is produced as low-energy clicks by the tongue. Furthermore, Rousettus ears lack the muscles and innervation required for self-deafening to improve information content of the reflected sound.
The profound differences between microbats and megabats in geographical distribution, behaviour, anatomy and physiology stimulated a controversial discussion whether the flying mammals truly are monophyletic. Tree building based on mitochondrial (Lin and Penny 2001 in Mol. Biol. Evol. 18, 684-688), genomic sequences incorporating the scarce available fossil data (Springer et al. 2001; Teeling et al. 2005 in Science 307, 580-584) and supertree algorithm (Emonds et al. 2007 in Nature 446, 507-512) suggests that bats have evolved from a common ancestor with megabats in a distinct clade. Fossilation of the most primitive bat found to date (a bat already capable of flight but not yet of echolocation, still with claws on all digits) is dated to have occurred 52.5 million years ago (Simmons et al. 2008 in Nature 451, 818-822). Powerful larnygal echolocation has evolved subsequently only once but was lost in the megabats where it was reinvented in its simple form only by Rousettus. 
Bats are vectors and reservoir for a number of important and emerging viruses, including members of the filoviridae (such as Marburg and Ebola virus), paramyxoviridae (such as Nipah virus), rhabdoviridae (such as rabies and European bat lyssavirus) and coronaviridae (the SARS-CoV).
Most surprising is the fact that bats appear not or only minimally to be affected by a variety of pathogens that usually are fatal to vertebrates.
For example, Ebola virus was detected in wild megabats collected at sites near to infected gorilla and chimpanzee carcasses. The megabats were positive for genomic RNA sequences from or antibodies against Ebola but did not display any disease symptoms (Leroy et al. 2005 in Nature 438, 575-576). Transfer of virus probably occurs via fruit contaminated by the megabats during foraging.
Nipah and Hendra viruses are associated with high mortality but, again, in megabats that serve as reservoirs there are no symptoms (Reynes et al. 2005 in Emerg. Inf. Diseases 11, 1042-1047). Microbats appear not to carry Nipah or Hendrah viruses.
According to the World Health Organisation, 55000 human deaths from rabies are reported annually. Rabies is invariably fatal to mammals with extremely rare and unusual exceptions: in spotted hyenas of the Serengeti a special, possibly attenuated strain of rabies has established endemic persistence (East et al. 2001 in Proc. Natl. Acad. Sci. U.S.A. 98, 15026-15031), and a single wild oncilla with antibody titers suggestive of exposure to rabies virus but otherwise clinically inapparent was captured in Bolivia (Deem et al. 2004 in J. Wildlife Diseases 40, 811-815). Certain bat species, however, frequently are found to carry rabies virus without overt symptoms (for example Poel et al. 2005 in Emerging Inf. Dis. 11, 1854-1859 for European bats and Messenger et al. 2002 in Clinical Inf. Dis. 35, 738-747). Rabies ecology is complicated and many wild and domestic animals are vectors depending on country and geographic region. In Latin America main vectors and reservoirs for rabies appear to be hemovorous (vampire) bats and dogs (Ito et al. 2001 in Virology 284, 214-222). Insectivorous bats are important vectors for cryptic rabies in developed countries: transmission of virus after encounter with a bat has not been realized until it is too late for post-exposure prophylaxis (Feder et al. 1997 in Lancet 350, 1300). Most fascinating and further highlighting significance of bats for rabies dissemination is a phylogenetic analysis suggesting that possibly an insect rhabdovirus transferred into an insectivorous bat, evolved into bat lyssaviruses and from there repeated further host switching into the carnivora has allowed rhabies virus to emerge as it is known in contemporary mammals (Badrane and Tordo 2001 in J. Virol. 75, 8096-8104).
Spread of an agent causing severe acute respiratory syndrome (SARS) in the human population nearly created a pandemic in 2002/2003. With rapid identification of the pathogen, a coronavirus named SARS-CoV, it was subsequently realized that SARS-CoV entered the human populatian via a zoonotic event at a Chinese meat market with civet cats as source (Guan et al. 2003 in Science 302, 276-278). Recent analysis indicate that fruit bats and microbats are reservoir for SARS-CoV (Li et al. 2005 in Science 310, 676-679); again, infection may have initiated via spill-over to other species after a pathogen evolved in bats where it does not cause disease.
The fatal suitability of bats as vectors may be due to a coincidental combination of behavioural, evolutionary and physiological properties:
Many bats tend to live in large communities at high population density thus facilitating repeated exposure, spread and maintenance of certain pathogens. Spread within a roost may be further enhanced or modulated if the act of echolocation generates an aerosol of pathogens suspended in saliva and mucus from mouth or nose of the animals. Transmission with aerolized pathogens may cause infection with low viral loads or unusual entry into the recipient (for example, mucosal infection with rabies or flavivirus rather than parenteral via bite or insect vector) and this may lead to persistent and subclinical infection.
Bats can fly and thus a carrier of a disease may cover large areas or gain more easily access to human shelters to transmit a pathogen. This propability for transmission is further increased by the long lifespan of bats.
Self-powered flight places a large burden on efficient metabolism. To conserve energy, some bats hybernate or reduce body temperature even for daily sleep. The adaptation to high metabolic rates, hypothermia by itself and possibly intermittent depression of the innate and adaptive immune system due to these adaptations may help viruses to establish subclinical persistence.
Finally, bats are an evolutionary very old order of the mammalia class. Difficult and enigmatic to trace via fossil and molecular records, the latest common origin of the various bat species has been estimated to have lived 89 million years ago in the late Cretaceous period (Bininda-Emonds et al. 2007 in Nature 446, 507-512). Major speciation of bats appears to have started within the K-T boundary (Teeling et al. 1995 in Science 307, 580-584), a geological signature assumed to have been caused by a catastrophic event approximately 65 million years ago. The K-T boundary separates sediments from the Cretatious and Tertiary periods and coincides with the extinction of dinosaurs and increase of plant and insect diversity—liberating ecological niches and providing new sources for foraging. Being an evolutionary old clade may translate into two properties with respect to suitability as disease vectors: their adaptive immune system may react to certain pathogens very differently compared to the immune system of most mammalia, and some of the more dangerous zoonotic agents may have decreased pathogenicity towards bats due to co-evolution with the flying mammals as reservoir.
In summary, bats are fascinating animals with significant impact on the infectious disease ecology, both as reservoir and vector. Shadowed by the huge taxonomic diversity of microbats, megabats form a unique clade within these unique mammals. Specifically megabats have been implicated as disease carriers for important pathogens such as filoviridae.
Many macroscopic determinants for suitability of bats as vectors have been discussed above. The individual cell also has been shaped by these circumstances. For example, energy expenditure of self-powered flight is high and physiology and biochemistry has to adapt to the increased metabolic requirement. It has recently been suggested that this adaptation extends to the individual cell (Organ et al. 2007 in Nature 446, 180-184): the genome of birds and bats is surprisingly small compared to other vertebrates. A small genome translates into a small nucleus and thus into a small cell volume. Diffusion of dissolved gases, nutrients and metabolites is more efficient in small cells.
On the other side of the evolutionary equation, some viruses that are serious threats today may have adapted to bats as reservoirs and thus evolved to find suitable receptors, cellular cofactors for genome replication, viral protein processing and maturation, and virion morphogenesis and egress.
Thus, properties of cell lines derived from bats may be of profound use from an industrial perspective: it is assumed that important infectious agents find a unique environment in bat cells especially from the Megachiroptera with respect to host range, productivity and formation or avoidance of cytopathic effect. An immortalized cell line derived from a Megachiroptera would be extremely beneficial to virus and vaccine research and to production of prophylactic or therapeutic vaccines or viral vectors. Furthermore, an immortalized cell line derived from a Megachiroptera may allow cell based assays for isolation of pathogens yet insufficiently characterized for PCR or serological diagnosis. Furthermore, we propose using bat cells with their naturally high metabolic advantages as industrial producer cells. To utilize and explore these properties one first has to generate such a cell line. With such a cell line, preferrably aided by modern proteomics and genomics, it is identify nodes and factors in the biochemical pathways that are instrumental for transfer of bat cell properties to common producer cells for viruses or proteins such as Vero or CHO. It is also possible to identify and characterize properties evolution has shaped in bats with respect to virus susceptibility and degree of or resistance against an infection. These factors, and the properties they confer, are transferred to suitable host cells from other species, avian, insect or human for example, for generation of therapeutic molecules, attenuated or targeted viruses, and viral vectors in therapeutic or prophylactic approaches.